Noncatalytic ester exchange reaction of beta-keto carboxylic acid esters



removed from the resulting ester,

2,693,484 Patented Nov. 2, 1954 NONCATALYTIC ESTER EXCHANGE REACTION OFBETA-KETO CARBOXYLIC ACID ESTERS Lowell O. Cummings, Henry A. Vogel, andAlfred R. Bader, Milwaukee, Wis., assignors to Pittsburgh Plate GlassCompany No Drawing. Application April 7, 1951, Serial No. 219,900

15 Claims. (Cl. 260-483) The present invention relates to methods offorming .esters of beta carbonyl acids and alcohols and it has OHO Asecond object of the invention is to provide a simple method of formingesters of higher alcohols containing for example or 12 and usually 16,18 and more carbon atoms per molecule.

A third object of the invention is to provide a method of forming estersof alcohols which is adapted to operate Without the use of catalysts andat moderate temperatures to obtain an exceptionally high yield ofdesired product in a state admitting of ready purification. v

A fourth object of the invention is to provide novel esters of betacarbonyl carboxylic acids and higher hydroxy compounds having anexceptionally high degree of United States Patent ()fifice functionalityand solubility and adapting them to organic reactions and syntheses.

A fifth object of the invention is to provide esters of alcohols ofexceptionally strong polarity that adapts them physically for use asemulsifiers, solubilizers, plasticizers and the like applications.

A sixth object of the invention is to provide novel esters of betacarbonyl carboxylic acids and higher al- I cohols.

A seventh object of the invention is to provide a method of formingesters of sterols which is operable without the use of excesses of thesterols.

These and other objects will be apparent from the followingspecification and the appended claims.

Prior art It has heretofore been customary to prepare esters of variousalcohols and carboxylic acids by a number of difl'erent methods such asdirect reaction between the desired acids and alcohols or betweenchlorides of the acids or the anhydrides of the acids and the alcohols.In some cases, desired esters have been obtained by interchange ofradicals between esters of carboxylic acids and lower alcohols withhigher alcohols.

In general these processes involved rather drastic conditions ofreaction, as, for example, high temperatures and/or the use of basic oracidic catalysts and the like. Moreover, in these processes conditionsof reaction often have complicated removal of the unreacted portions ofthe reactants, or the catalyst residues from the reaction products andfrequently these impurities could not be Often the reaction wasincomplete and poor yields of the desired product were obtained. Theseditficulties were quite pronounced in the production of esters of highermolecular weight alcohols, for example those containing at least 6 orusually -more carbon atoms. Moreover,'the processes usually involved theuse of great excesses of the alcohol which was being subjected toesterification. Obviously in dealing with scarce and expensive compoundssuch as sterols, this was highly objectionable.

The present invention According to the present invention, it has beendiscovered that esters of high molecular weight can be prepared in highpurity and in almost quantitative yield by interacting under mildconditions an ester of an enolizable beta carbonyl or beta keto'carboxylic' acid and a lower aliphatic (preferably saturated) alcoholcontaining, for example, up to 4 carbon atoms with an alcohol of higherboiling point than such lower alcohol (preferably at least 20 C. higher)which forms a corresponding ester having a boiling point above about 230C. while maintaining in the reaction mixture at least one or moreequivalents of the ester for each equivalent of higher alcohol.

In order. to avoid production of ketones and other byproducts and toobtain approximately quantitative yields, it is necessary that thetemperature of the reaction should be kept low. For best results(maximum yield and purity of product), the temperature of reactionshould not exceed about 150 C. and preferably should be below or C.

Somewhat higher temperatures may be used with cer tain alcohols providedspecial precautions are observed to remove evolved lower alcohol fromthe reaction mixture substantially as rapidly as evolved. Suchprecautions are more fully explained below.

According to a further embodiment of the invention, it has been foundthat maximum yield and purity of ester is obtained when the evolvedlower alcohol is swept rapidly from the reaction mixture. This may beaccomplished by distilling the lower alcohol under conditions such thatthe partial pressure. of the lower alcohol vapor is maintained belowatmospheric pressure. For example, the reaction mixture may be blownwith an inert gas such as carbon dioxide, nitrogen, etc. to cause rapiddistillation of evolved lower alcohol. Alternatively or in conjunctiontherewith, a subatmospheric pressure may be maintained over the reactionmixture whereby to promote distillation of the evolved lower alcohol.These precautions are of especial importance where the temperature ofthe reaction mixture is allowed to rise to a relatively high value, forexample 120-l60 C. However, purer products are generally obtained byrecourse to these precautions even when the reaction temperature isbelow 120 C.

Typical esters which are prepared are the esters of acetoacetic acid.However, the esters of other beta keto acids such as are listed belowalso may be prepared.

To insure good yields, excesses of the alcohol to be reacted with theacetoacetic ester are avoided. Indeed, great excesses of the acetoaceticacid ester component may be employed and if care is exercised toeliminate, or at least sufiiciently to reduce in the reaction zone therelative concentration of the alcohol freed, with respect to that of theinitial beta keto ester, quantitative interchange of alcohol radical canbe attained.

The reaction involved may be represented by the general equation:

The several groups R R R and R will be defined later. As previouslystated, in order to obtain the most complete reaction, we find itconvenient to use an excess of the beta keto ester of the lower alcohol.

BETA KETO ESTERS Beta keto esters which may be employed to effectesterification of alcohols include various esters which contain a ketonecarbonyl group in the beta position already referred to. The generalstructure of the esters may be represented by the formula taken from theabove Equation A which is as follows:

In the formula, group R may be aliphatic, aromatic or aliphatic oraromatic groups which may or may not contain substitute groups. Examplesof R groups are:

and other halogen substituted hydrocarbon radicals, RNHz, RCHO, etc.

R also frequently is hydrogen but it can also be hydrocarbon orsubstituted hydrocarbon such as methyl, ethyl, propyl, butyl, chloro,amino, chloromethyl, benzyl, phenyl or the like or derivatives thereof.the hydrogens of the alpha carbon atoms can be replaced by substituents.The remaining hydrogen atom is an active atom essential to the esterinterchange reaction and must be retained.

R is usually the labile radical which is adapted to be replaced in theester interchange. These functioning groups usually are of low molecularweight, e. g., l, 2, 3, or possibly 4 carbon atoms in a saturated orunsaturated aliphatic substituted or unsubstituted hydrocarbon chain.

Examples of appropriate liquid beta carbonyl esters suitable for use inthe practice of the invention include the following compounds:

Table A Methyl, ethyl, n-propyl, isopropyl, allyl, methallyl, crotyl,

propargyl, 2-chloroethy1, 2-fluoroethyl, 2-nitropropyl OOOH COCHzCOOH Ithas been found that a beta carbonyl ester which is doubly substituted inthe alpha position thus containing no active hydrogen and being unableto enolize, gives no ester interchange with alcohols under theconditions of the present invention. Such an ester is methyl dimethylacetoacetate of the formula:

Esters having structures or molecular weights somewhat similar toacetoacetic ester, but being dissimilar in not having one or more activehydrogen atoms, have been found to be non-reactive under the conditionsherein Only one of contemplated. For instance, ethyl n-butyrate has a molecular' weight almost identical to that of methyl acetoacetate butgives no reaction. Ethyl lactate and methyl levulinate havestructures'somewhat similar to methyl acetoacetate being respectively:

Methyl levulinate Neither ethyl lactate nor methyl levulinate givestransesterification under the conditions of the present invention.

ALCOHOLS CAPABLE OF ESTER INTERCHANGE WITH BETA CARBONYL ESTERS Manyhydroxy compounds of relatively high molecular weight may be treatedaccording to this invention. Typical are compounds having the formula R(OH)x (from Equation A) where (OH) is an alcoholic OH group, R contains6 or more carbon atoms and X is a number denoting the number of hydroxylgroups in the molecule. These easily, quickly and without catalystsundergo ester interchange with beta carbonyl esters to provide higheresters of beta carbonyl acids. The sterols and certain of the relativelylong chain alcohols and hydroxy compounds such as occur in or arederived from glyceride oils, tall oil waxes and wool fats or the likeare outstanding examples of such compounds. These are compounds ofconsiderable molecular weight, containing at least 12 and usually 16,18, 27 or more carbon atoms. It was quite surprising that these hydroxycompounds of such high molecular weight would so easily undergo esterinterchange.

The sterols can be regarded as being derived from cyclopentanophenanthrene:

'or its perhydro derivatives by appropriate shifting or or itshydrogenated derivatives.

These hydroxy compounds are often comparatively sensitive to hightemperatures and other conditions. However, many of them are importantstarting compounds in the synthesis of hormones and other biologicals.Yet in some of the reactions to which the compounds are subjected it isdesirable to protect the hydroxyl oxygen from loss or from conversion tocarbonyl form. It may also be desirable to convert the hydroxyl to esterform in order to increase the polarity of the compound or to providereactive, or labile groups.

It has now been discovered that these higher alcohols can easily besubjected to esterlfication with beta carbonyl esters at very moderatetemperatures and without resort to catalysts to provide esters of greatutility.

Examples of higher alcohols which can be esterified with beta carbonylesters by ester interchange include:

Table B Sterols such as:

Cholesterol Beta sitosterol Stigmasterol CholestanolEpidehydroandrosterone Ergosterol Epicholestanol Coprostanol CortisoneCholic acid Desoxycholic acid Steroid Sapogenines Steroid intermediatesTriterpene alcohols such as:

Agnosterol Lanosterol Aliphatic compound containing at least 6 andusually containing 16 or more carbon atoms and containing alcoholichydroxyl groups, such as:

Octadecyl alcohol Lauryl alcohol Ceryl alcohol Cetyl alcohol Carnaubylalcohol Lignoceryl alcohol Polyhydroxy compounds such as:

Decamethylene glycol Glycerine Ethylene glycol Polyethylene glycol andpolyethylene oxide resins or waxes and like waxy resins which aresoluble in solvents of fats Ether alcohols such as: Butyl carbitolPropyl carbitol Hydroxy glyceride oils such as:

Castor oil Monoand di-glycerides which are soluble in solvents of fatsSynthetic hydroxy glycerides Cyclic and polycyclic alcohols CyclohexanolHydroxy decalin Polyhydric alcohol-polybasic acid resins such asglycerol phthalate, glycerol or glycol maleate or monobasic acidmodified resins of this character Diamyl carbinol Diethylene glycol1,2-dichloropropanol 3 Pentaerythritol Linoleyl alcohol Nitro alcoholssuch as:

Z-methyl, Z-nitropropyl alcohol 2-nitrobutyl alcohol and others.

When it is desired to avoid alkylation rather than, or in conjunctionwith, esterification, alcohols which contain a phenyl group directlylinked to the carbinol atom thereof should not be used. Unsaturatedalcohols such as allyl alcohol, methallyl alcohol, crotyl alcohol, etc.,may be used effectively to produce the esters contemplated. In somecases these esters may tend to rearrange after formation to ketonederivatlves.

It is desirable that the esters produced by mterchange between theoriginal beta carbonyl esters and the h1g h er alcohols be of a boilingpoint above that of the initial beta keto ester (compound 1), forexample, the ester produced preferably should boil at a temperatureabove 230 C. at 760 millimeters pressure. Th s permits readypurification of the product by simple d1st1llat1on or by crystallizationor other means.

Obviously the hydroxy compound WhlCh 18 to undergo interchange with thebeta carbonyl compound should be soluble in the latter, or at leastshould be soluble in solvents that are mutually compatible with betacarbonyl compounds.

CONDITIONS OF REACTION The conditions of reaction employed to efiect theester interchange betweenthe hydroxy compounds and beta carbonyl esterssuch as beta keto esters may vary, dependent upon the carbonyl ester andthe hydroxy compound employed in the reaction. However, the conditions,in most cases are relatively mild.

Catalysts of reaction are not required and usually it is desirable tooperate without them. However, such catalysts may be present if purityof product is not important.

The temperature of reaction should be sufficiently high to drive oil thelower alcohol quite rapidly. Preferably, it should be driven 01fsubstantially as fast as it is liberated in the reaction mixture. Thetemperature should also be below the point of decomposition of thereactants, or the desired product. A good average temperature isapproximately to C. which is near that of an ordinary steam bath. Thetemperature can also be reduced below this value. However, it is to beunderstood that as the temperature approaches or is reduced below thenormal boiling point of the lower alcohol evolved in the system, it isdesirable to apply vacuum in order to promote removal of the latteralcohol. Higher temperatures preferably below C. and in any event belowC. are permissible under the conditions explained heretofore.

The approach of the upper limit of the temperature of decomposition canusually be detected by a darkening of the reaction mixture. If anytendency so to discolor is observed, the temperature should be reduceduntil it ceases. It is usually preferred to employ a temperature abovethe boiling point of the lower alcohol involved in the system. Thisfacilitates removal of the latter.

To obtain a very high yield of desired ester of the higher alcohol, theconcentration of the lower alcohol in the reaction mixture should not beallowed to exceed 33 mole percent of the acetoacetic ester of suchalcohol in the mixture. It is even desirable that the precentage be asmuch lower than this value as can reasonably be attained. If theconcentration is reduced to 5 molar percent or even to 1 or 2 molarpercent or less (based upon the beta keto ester of the lower alcohol),still better yields can be attained.

Several methods are available to attain these low concentrations of theevolved lower alcohol without unduly increasing the temperature of thereaction mixture. For example, the system can be placed under fairlyhigh vacuum thus stripping off the lower alcohol as it is formed whilepermitting the temperature to stay relatively low. Beta keto ester oflower alcohol carried over as a vapor in the lower alcohol stripped offcan be condensed and returned. In this Way, the concentration of theoriginal beta keto ester in the system is maintained.

It is likewise contemplated to strip off lower evolved alcohol byblowing the reaction mixturewith a non-reactive vapor or gas, e. g.,nitrogen, CO2, or the like. Steam in substantial amounts is usually tobe avoided.

Still another convenient method comprises dilution of the alcohol ofreaction by employing a high molar excess of the beta keto ester of thelower alcohol. For example, the excess may be 0.1 to 5, 10 or even 100fold of the molecular ratio of the beta keto ester with respect to theoriginal higher alcohol undergoing ester interchange. The excess can beadded initially or it can be added as the reaction proceeds.

Combinations of these several methods are within the scope of thisinvention. For example, a 2 to 100 mole excess of beta keto ester can beemployed and at the same time the alcohol of reaction can be removed asit is evolved, thus maintaining an extremely low percentage of the loweralcohol in the system. Such stripping may be effected by simpledistillation at atmospheric pressure, by vacuum distillation or byblowing with non-reactive gas or vapor.

By properly reducing the concentration of the evolved lower alcohol inthe system, it is possible to obtain yields of higher ester of beta ketoacids of 90% or higher up to practically quantitative values, e. g., 98or 99%, without discoloration of the product or the reactants.

If care is observed to maintain the reaction temperature reasonably lowand at the same time to distill off under vacuum or otherwise to remove,or decrease the concentration of the lower alcohol evolved by reaction,highly efiicient ester interchange can be eifected with equimolar ratiosof the higher alcohol and the beta keto ester of lower alcohol or withonly a slight excess of the latter. However, it is usually moreconvenient to operate with an excess which is substantial, e. g., 10% orpreferably larger (upon a molar basis) of the starting mote thedistillation within the permissible temperature limits. A pressure ofabout 5 to 50, e. g., millimeters of mercury is usually satisfactory fordistilling 01f this excess of beta keto ester but such other pressuresas will remove the excess ester at permissible temperatures may beemployed. The distillation may be conducted at or near'the originalreaction temperature. The distillation of the excess beta keto ester oflower alcohol is important because it also distills off any loweralcohol in the system, thus reducing the concentration of the latterwith respect to the original beta keto ester still present and assuringthat the ester interchange reaction is completed at moderatetemperatures.

In general the reaction is conducted at a temperature above about 50 C.At temperatures ranging from 50 to 130 C. or above the reaction usuallyproceeds to substantial completion in about 3 to 48 hours. Where lowertemperatures are used, for example room temperatures or below, thereaction is much slower and several weeks may be required to achievesubstantial reaction and even then use of a substantial excess (100% ormore) of keto ester generally is required.

The main features involved in the process as herein disclosed may besummarized as follows:

1. Selection of an alcohol to be subjected to ester interchange whichdoes not undergo side reaction and which is substantially of higherboiling point than the alcohol liberated by reaction.

2. The amount of beta carbonyl ester should be in at least an equimolarproportion with respect to the alcohol to be subjected to esterinterchange and preferably it should be in excess. In production ofesters of many alcohols, it is necessary to use an appreciable excess,for example 50% or more, of beta keto ester in order to dissolve thealcohol being esterified and/or to insure improved yield.

3. The concentration of evolved alcohol in the reaction mixture shouldbe maintained as low as is feasible, e. g., not in excess of about 33molar percent and preferably less with respect to the original amount ofthe beta keto ester of lower alcohol. This may be effectivelyaccomplished in several ways, as for example by distilling ofl the loweralcohol as formed under conditions such that the partial pressure of thealcohol vapor is below atmospheric, at least during the later stage ofthe reaction.

4. Catalysts of reaction are not necessary and usually are not employed.

5. The temperature of ester interchange should be moderate, e. g., 50 to120 C. and usually under no circumstances above 160 C. Satisfactoryupper limits of temperature are determinable by observation for theinitiation of decomposition reaction.

6. Time or" reaction should be maintained until the lower alcohol ceasesor substantially ceases to evolve.

7. Solvents are not ordinarily necessary in the reaction. The beta ketoester of a lower alcohol, however, in a sense constitutes a reactionsolvent. It will be apparent that non-reactive liquid media may also beemployed as solvents if so desired.

8. It is desirable, at the conclusion of the reaction, to distill offany excesses of the beta keto ester of lower alcohol present in thereaction mixture along with any residual lower alcohol evolved by thereaction by distillation at a lower temperature. If this latterprecaution is observed, any unreacted higher alcohol still present inthe system will be induced to undergo reaction and thereby carry thereaction substantially to completion.

The following examples illustrate the application of the principles ofthe invention:

EXAMPLE I In this example, grams of cholesterol and 100 grams of methylacetoacetate were heated together in the absence of catalyst in a roundbottom flask with open neck, at 90 to 100 C. Methyl alcohol was expelledas the reaction proceeded. At the conclusion of 8 hours, the excess ofmethyl acetoacetate was removed by vacuum distillation at a pressure ofabout 15 millimeters of mercury and there was obtained 23 grams of awhite solid which had a melting point of 91 to 93 C. This product wasdissolved in aqueous acetic acid and recrystallized to obtain a furtherpurified compound melting at 93 to 94 C. The specific rotation a inchloroform was -33. The compound was cholesteryl acetoacetate of veryhigh purity.

EXAMPLE II A mixture of 10 grams of cholesterol and 50 grams of ethylacetoacetate was heated on a steam bath for 3 hours. The excess of ethylacetoacetate was removed by distillation at a pressure of 10 millimeters(absolute). There remained 11 grams of a white solid which was identicalwith the product obtained in Example I, being cholesteryl acetoacetate.Saponification with alcoholic potassium hydroxide gave quantitativeyields of choles terol indicating the ester structure of the cholesterylacetoacetate. Analysis by other methods well known in the art furnishfurther proof of the structure of the reaction product. a

The acetoacetates of higher alcohols, in general, possess greatersolubility than the parent alcohol, as well as greater solubility thansuch conventional ester derivatives as acetates or benzoates. This makesacetoacetate derivatives of sterols useful intermediates in steroidsyntheses because of greater ease of handling in solutions for purposesof crystallizing or of conducting other synthetic reactions onsolutions. For example. in the following table are given the comparativesolubilities of cholesteryl acetoacetate and cholesteryl acetate in anumber of solvents. The volume of each solvent in cubic centimeters ormilliliters required to dissolve 1 gram of the cholesteryl ester atreflux temperature is given.

Acetone 3 Less than 1 cc. 70 20 cc.

13 Less than 2 cc. Metharaol-l-Isopropyl Ether (Equal vol- 9 D0.

urnes Methanol-l-Acetone (Equal volumes) 17 Do.

(ce.=rnilliliters.)

This increased solubility of a sterol derivative is of particularadvantage when purifying such materials by solvent crystallization sincethe volume of solvent required to dissolve the sterol derivative is from/3 to ,4, as large when using the acetoacetate rather than the acetateof the sterol.

It is well known that beta keto acids and their esters are metabolicintermediates. Compounds such as acetoacetic esters and acetonedicarboxylic esters have been isolated as products of metabolism. Estersof beta keto acids and sterols, therefore, may be metabolicintermediates and may have therapeutic value.

It is to be observed in these examples that no catalysts of reaction arerequired in the ester interchange. The temperatures are very mild. Thereaction is thereby distinguished from conventional ester interchangeswhich are catalyzed by alkaline or acid catalysts and require highertemperatures. The proportion of higher alcohol is also much less thanmolar. The reaction by ester interchange as herein disclosed s also animprovement upon conventional reactions mvolvedin the preparation ofesters of higher alcohols 111 which acid chlorides or acid anhydridesare caused to react with the alcohol. In this latter type of reaction,the stronger acid compounds may be difiicult to handle and the excess ofreactant cannot be readily recovered. in the present instance, theexcess of ethyl acetoacetate or other beta carbonyl ester can readily berecovered by simple distillation, with only quantitative amounts beingconsumedin the interchange reaction. The reaction product likewise isnot contaminated by catalyst or by-products from catalyst removal ordestruction.

The followmg additional examples illustrate further embodiments of theinvention:

acetoacetate were heated on a steam bath and under an air condenser,under which conditions the methyl alcohol in chloroform equals 44. Thisproduct was stigmasteryl acetoacetate.

EXAMPLE IV Two grams of beta sitosterol having a melting point of 136 to137 C. and 20 grams of ethyl acetoacetate were heated on a steam bathfor 18 hours. The reaction product was stripped of ethyl acetoacetateand any residual ethyl alcohol by vacuum distillation and there remaineda white solid product constituting 2.2 grams and this was recrystallizedfrom petroleum ether admixed with methanol to provide a product in theform of white shining platelets of a melting point of 99 C. and aspecific rotation at 25 C. in chloroform of -24. The product was betasitosteryl acetoacetate. An identical product was obtained by use ofmethyl acetoacetate as the beta carbonyl ester.

EXAMPLE V One hundred milligrams of cholestanol, melting in a range of140 to 142 C. was treated with 10 grams of methyl acetoacetate byheating the mixture on a steam bath for 4 hours. Upon distillation ofthe excess of methyl acetoacetate, there remained a quantitative yieldof cholestanyl acetoacetate in the form of white platelets of a meltingpoint of 97 C. and of a specific rotation at 25 C. in chloroform of +12.

EXAMPLE VI In this example, epidehydroandrosterone was admixed with amolar excess of methyl acetoacetate and heated on a steam bath for 18hours. The excess of methyl acetoacetate was distilled under vacuum andthere remained a solid product which was recrystallized from methanol toprovide feathery white crystals of epidehydroandrosterone acetoacetatemelting at 163 C. The specific rotation a in chloroform was +1".

EXAMPLE VII In this example, 5 grams of oetadecyl alcohol and 30 cc. ofmethyl acetoacetate were heated on a steam bath for 24 hours. The methylalcohol of reaction was continuously removed. At the conclusion of thistime, the excess of methyl acetoacetate was distilled under vacuum untilan oily residue remained. The residue was taken up in a mixture of 30cc. of methanol, cc. of acetone, and 6 cc. of water. Upon cooling thesolution, white crystals in a yield of 6 grams and of a melting point of40 to 40.5 C. precipitated. These crystals were octadecyl acetoacetate.

EXAMPLE VIII Fifty grams of cold pressed castor oil (largely atriglyceride of ricinoleic acid) and 150 grams of methyl acetoacetatewere heated in an open necked glass flask on a steam bath for a periodof 4 hours. The mixture at that point was a clear solution which wasstripped of methyl acetoacetate and residual methyl alcohol bydistillation at 10 millimeters mercury pressure (absolute) to leave alight yellow oil weighing 62 grams. This product is castor oilacetoacetate and an infra-red analysis showed the complete absence ofhydroxyl groups in it. The plasticizing action of this product was foundto be good in the following compositions:

50 grams of 32% solids clear lacquer of /2 second nitrocellulose inmixed solvents (butyl acetate, ethanol, isopropyl acetate and toluene)10 grams butyl acetate 10 grams castor oil acetoacetate.

EXAMPLE IX Eight grams of decamethylene glycol and 45 cc. of methylacetoacetate were heated on a steam bath for 18 hours. After vacuumdistillation of the excess methyl acetoacetate and residual methylalcohol, there remained a waxy solid of a melting point of 31 to 33 C.which, after a single crystallization from methanol, melted at 33 to 34C. This product was decamethylene diacetoacetate.

EXAMPLE X Eight grams of cyclohexanol was substituted for decamethyle eglycol in Example IX and the mixture was heated art previouslydescribed. The product as obtained by dis llation of the excess methylacetoacetate was a water white liquid boiling Within a range of 126 to129 C. at a pressure of 15 millimeters (absolute) of mercury. The ndexof refraction at 25 C. was 1.45765.

EXAMPLE XI In this example, a non-reactive solvent was employed. Amixture of 5 grams of cholesterol and 25 cc. of methyl acetoacetate insolution in 250 cc. of xylol (inert solvent) was heated on a steam bathand under an air cooled condenser designed to pass evolved methylalcohol and to return reactives and solvents to system for 18 hours. Atthe conclusion of the reaction period, the methyl acetoacetate and thexylene were stripped by distillation under vacuum and there remained 5.9grams of a white solid which, after one recrystallization from aqueousacetic acid, melted at 92 to 93 C. and which was identical withcholesteryl acetoacetate prepared without solvents as described inExample I.

EXAMPLE XII A mixture of grams of polyethylene glycol of approximatelymolecular weight of 200 and 400 grams of methyl acetoacetate was heatedunder slight negative pressure on a steam bath for 15 hours. The excessmethyl acetoacetate and any residual methyl alcohol were then removed byvacuum distillation and there remained grams of a water soluble liquid.This product was poly ethylene acetoacetate having a saponificationvalue of 359.

EXAMPLE XIII In this example, 100 grams of butyl carbitol (diethyleneglycol monobutyl ether) was reacted with excess methyl acetoacetateunder the conditions described in Example XII. After removal of theexcess methyl acetoacetate, there remained a water white liquid butylcarbitol acetoacetate having a saponification value of 342.

EXAMPLE XIV tion n =1.4372.

EXAMPLE XV The use of esters of benzoyl-acetic acid, which are betacarbonyl compounds, in the transesterification has been referred to. Inthis example, 5 grams of cholesterol and 30 grams of ethylbenzoyl-acetate were heated at steam bath temperature for 20 hours.Removal of the unreacted ethyl benzoyl-acetate by vacuum distillationleft 6.4 grams of cholesteryl benzoylacetate, which aftercrystallization from a butyl acetate-ethanol mixture melted at 151 C.

EXAMPLE XVI Five grams of stearyl alcohol and 25 grams of ethylbenzoylacetate were heated on the steam bath for 24 hours. The excessethyl benzoylacetate was removed by vacuum distillation. The residue wastriturated with methanol, filtered, and dried, yielding 6.5 grams ofstearyl benzoylacetate. After crystallization from acetone, 1t melted at555 7 C. and had a saponification value of 180.

EXAMPLE XVII Two grams of ethyl acetone dicarboxylate and 2.7 grams ofstearyl alcohol were heated on a steam bath in an open neck flask withremoval of ethyl alcohol for 16 hours. The mass was then dissolved inethanol, cooled and filtered. There were obtained fine crystals of di'stearyl acetone dicarboxylate which melted at 65 C. and had asaponification value of 343.

EXAMPLE XVIII This example illustrates the employment of inert gas tostrip oft lower alcohol as it is formed and moderate temperatures ofreaction in the preparation of an ester of menthol and acetoacetic acidby interchange reaction between the alcohol and methyl-acetoacetate inmolecular ratio. In the reaction, .2 mole of menthol and .2 mole ofmethyl acetoacetate were heated to a temperature of 95 C. The reactionwas continued at that temperature while inert gas (from butanecombustion) was bubbled in vigorously or at least sufficiently rapidlyefiectively to sweep out methyl alcohol as it was liberated. (Inert gascan be replaced by vacuum, if so desired.) In this instance, thereaction was continued for 24 hours.

A yield of 94% menthyl acetoacetate having a melting point of 24 to 27C. was attained. This product was further purified by crystallization toprovide a product of a melting point of 30 to 32 C.

EXAMPLE XIX In this example, a large excess of ethyl acetoacetate wasemployed at moderate temperatures of reaction- The proportions were:

Moles Menthol .1 Ethyl acetoacetate 15 The temperature of reaction was98 C. Neither inert gas nor vacuum were employed. Any ethyl alcoholvaporized was allowed to escape, but no effort was made to promotevaporization. The reaction was continued for 24 hours to assurecompletion without recourse to testing. The reaction mixture wasdistilled at 15 mm. (absolute) and to 112 C. to remove excess ethylacetoacetate together with any residual ethyl alcohol in the mixture. Anexcellent product melting in the range of 2629 C. and in a yield of 99%was attained. This product could be further purified by crystallizationto form a product of a melting point of 30 to 32 C.

EXAMPLE XX Admix .2 mole of menthol and .2 mole of methyl acetoacetateand heat to 150 C. while blowing with inert gas to remove methyl alcoholas rapidly and thoroughly as practicable. (In lieu of inert gas, avacuum can be applied with similar results.) Reaction is complete in 5hours or less. A yield of 99% of a material melting at 20 to 23 C.results. This material is a solid and can be purified bycrystallization. However, it is less pure than that obtained in ExamplesXVIII or XIX.

EXAMPLE XXI This example illustrates a control run. In it, a mixture of.1 mole of menthol and .1 mole of ethyl acetoacetate were heated atatmospheric pressure Without inert gas, to a temperature of 150 C. for2.5 hours. The reaction mixture was distilled at 15 millimeters ofmercury while the temperature was increased to 160 C. The productremained as a 42% yield of an oily residue in the flask. It was oilyeven at C. and was difiicult to purify. The temperature of reaction wastoo high.

EXAMPLE XXII This was essentially repetition of Example XXI except thatreaction was continued for hours. Distillation was stopped at 152 C.,because an excessive evaporation of the reaction mixture had alreadyoccurred. The yield of product was 18%. This was an oil which wasdiflicult to purify.

12 EXAMPLE XXIII This was also a control test in which a low temperatureof reaction and a long period of reaction were employed. Both inert gasand vacuum were omitted during the reaction. The reaction mixtureconsisted of .1 mole menthol and .1 mole ethyl acetoacetate. The mixturewas maintained at 98 C. for 24 hours. The mixture was then subjected toa vacuum of 1S millimeters of mercury (absolute) to 160 C. Thedistillation residue constituting the menthyl acetoacetate productconstituted a yield of only 24%. This product had a melting point of 27to 30 C.

This experiment was repeated, but distillation was conducted at 140 C.The yield was 37% and the product had a melting point of 30 to 32 C.

EXAMPLE XXIV In this example, lauryl alcohol which is a C-12 alcohol wasemployed as the higher alcohol in the ester interchange reaction. Laurylalcohol in a proportion of 5 grams was admixed with 500 grams of methylacetoacetate and the mixture was heated on the steam bath for 20 hours,the evolved methyl alcohol being allowed to escape during the reaction.At the conclusion of the period, the excess methyl acetoacetate wasevaporated at a pressure of 10 millimeters of mercury (absolute) and theresidue in the distillation flask was then distilled to yield 7 grams ofa water white liquid lauryl acetoacetate.

EXAMPLE XXV In this reaction, ester interchange was effected betweencholesterol and methyl acetoacetate. The reaction mixture comprised 10grams of cholesterol and cc. of methyl acetoacetate, the mixture beingheated on the steam bath and at atmospheric pressure for 15 hours.During the reaction, inert gas was bubbled through the reaction mixtureto effect the thorough removal of evolved methanol from the zone ofreaction. Finally, the excess methyl acetoacetate was removed by vacuumdistillation to yield 12 grams of a white solid cholesteryl acetoacetateof a melting point of 91 to 93 C.

EXAMPLE XXVI This example illustrates the employment of vacuum duringthe course of the ester interchange for purposes of more thoroughlyremoving the lower alcohol as it is evolved. In the reaction, 10 gramsof cholesterol were again admixed with 100 cc. of methyl acetoacetateand the mixture was heated upon the steam bath for 15 hours at apressure of 40 millimeters of mercury (absolute). During the course ofthe reaction, methyl alcohol was evolved and distilled off andcholesteryl acetoacetate was formed. The yield and the purity of theproduct were practically identical with those obtained in Example XXV.

It is likewise contemplated to employ as a source of sterols or steroidbodies for use in the practice of the invention various glyceride oilmixtures containing sterols in substantial amounts. For example, a soapstock which normally contains considerable amounts of sterols, such ascholesterol, may be treated with methyl or ethyl acetoacetate inaccordance with the provisions of the invention to form esters of theketo acid in admixture with glycerides of fatty acids. The tempera turesof reaction correspond to those herein disclosed. The conditions ofreaction likewise in other respects, are similar to those of theexamples as herein presented. Many other mixtures of fat-like productslikewise include sterols which are susceptible of treatment inaccordance with the provisions of the present invention.

Wool fat, for example, includes considerable amounts of cholesterol andit is contemplated to treat such cholesterol-containing material with anexcess of ethyl or methyl acetoacetate at temperatures near the boilingpoint of water to form cholesterol esters in the mixture. Thesecholesterol esters can be recovered by solvents or by other appropriatemethods.

Likewise, tall oil as obtained in the digestion of paper pulp is rich insterols and notably in beta sitosterol. The distillation residueobtained after partial distillation of the rosin acids and fatty acidsof tall oil is highly enriched in beta sitosterol. This crude mixturecan be treated with methyl 91" ethyl acetoacetate to provide esters 13in admixture with rosin acids, fatty acids and the other impurities ofthe tall oil residue.

Usually it is preferable to operate with more concentrated forms of thesterol or steroid compound. For example, beta sitosterol has heretoforebeen recovered from tall oil and tall oil distillation residues bysolvent fractionation of crude tall oil. A convenient method ofobtaining sterols, e. g., beta sitosterol, from tall oil or tall oildistillation pitches comprises esterifying the crude material with alower alcohol, e. g., methyl alcohol, selectively to esterify fattyacids, contacting the mixture with countercurrently flowing streams ofnaphtha and furfural in a tower, separating off at one end a solution offurfural containing in solution a concentration of rosin acids andseparating off at the other end, naphtha containing in solution anenrichment of esters of fatty acids and ungsaponifiable materialincluding beta sitosterol. The naphtha can be recovered by evaporation.The mixture of esters and unsaponifiable matter can be treated withalkali, e. g., caustic soda, to saponify the esters and the residualrosin acids in the mixture. The unsaponifiable matter is separated bydissolving the mixture in an aqueous alcohol, e. g., aqueous isopropylalcohol and extracting out the unsaponifiable material in a solvent suchas naphtha, and evaporating the naphtha. If purer sterols are desired,they can be recovered by crystallizing them from a solvent of sterols.In many cases, a relatively pure product has been obtained. Thefollowing examples illustrate the application of the principles of theinvention in the preparation of beta keto esters of a crude or purifiedbeta sitosterol.

EXAMPLE XXVTI One hundred grams of unsaponifiable' fraction of tall oilwhich consisted largely of beta sitosterol together with some higheraliphatic alcohols and other materials was heated with 200 grams ofmethyl acetoacetate to 100 C. for /2 hour. The excess methylacetoacetate was then distilled off under a pressure of millimeters ofmercury (absolute) to obtain a residue of 103.6 grams of a materialcontaining the desired ester of acetoacetic acid and beta sitosterol.

EXAMPLE XXVIII 5.0 grams of stearyl alcohol and grams of methylethylacetoacetate CIhCOCH(C2H5)COzCH3 were heated on a steam bath for 48hours, the evolved methanol being distilled oif. The unreacted lowerbeta-keto ester was then removed by distillation in vacuo, and theresidue was dissolved in acetone and the solution poured into water.

The white solid which precipitated was filtered, washed and dried.Treatment of this product with alcoholic KOH showed this material toconsist largely of stearyl ethylacetoacetate.

EXAMPLE XIX EXAMPLE XXX 2.7 grams of stearyl alcohol and 2.0 grams ofethyl acetonedicarboxylate were heated on the steam bath in an openflask for 16 hours. The product was dissolved in hot ethanol and thesolution cooled, after which the white solid formed was filtered, washedand dried to yield distearyl acetonedicarboxylate. This solid melted at58-60 C., and had a saponification value of 343. This material onrepeated crystallization from a mixture of methanol and acetone meltedat 64.5-65.0 C.

EXAMPLE XXXI 10 grams of cholesterol and 100 grams of diethyl acetylsucciuate CaH50C)C-CH2CH2(CUCH3)COOC2H5 were heated on the steam bathunder a 10 millimeter absolute pressure for 64 hours. 93.5 grams ofunreacted lower 14 beta-keto ester was then removed by distillation invacuo, and the residue was dissolved in 50 milliliters of ethanol,cooled and the white solid filtered, washed with milliliters of ethanoland dried. The solid product, cholest1e6r5yl ethyl actyl succinate, hada saponification value of EXAMPLE XXXII EXAMPLE XXXIII 57 milligrams ofcortisone and 50 milliliters of methyl acetoacetate were heated on asteam bath for 16 hours. The unreacted methyl acetoacetate was thenremoved by distillation in vacuo, and the residue on crystallizationfrom aqueous ethanol yielded shiny platelets of cortisone acetoacetatewhich melted at 112114 C.

EXAMPLE XXXIV 325 milliliters of diacetone alcohol and 1000 millilitersof methyl actoacetate were heated on the steam bath for 24 hours. Theunreacted starting materials were then removed by distillation in vacuoand the flask residue on distillation yielded water-white diacetonylacetoacetate,

boiling at l27 C. at 10 millimeters absolute pressure, and having arefractive index N =1.4424.

Its ultraviolet absorption characteristics are as follows:

)\ ethanol 2 max 241.5 (log E=3.07); 306.5 (log E=2.34)

EXAMPLE XXXV 3.87 grams of cholesterol and 23.22 grams of methylacetoacetate were heated with 101.2 milligrams of triethylamine at 98 C.for 4 hours, using a water condenser. Then 50.0 milliliters of methanolwas added, the solution was cooled overnight at 23 F., the white solidwas filtered, washed with 50 milliliters of methanol and dried. Thissolid was cholesteryl acetoacetate.

EXAMPLE XXXVI The process of Example XXXV was repeated substituting 98.0mllhgrams of concentrated sulfuric acid for the triethylamine. Theproduct was cholesteryl acetoacetate.

EXAMPLE XXXVII The process of Example XXXV was repeated substitutmg 38.6milligrams of sodium cholesterate for the triethylamine. The product waslargely cholesteryl acetoacetate.

EXAMPLE XXXVIII The process of Example XXXV was repeated, substituting185 milligrams of benzene sulfonic acid hydrate for the triethylamine,and heating the reaction mixture at 98 C. for 3 hours. The product waslargely cholesteryl acetoacetate.

EXAMPLE XXXIX 3.87 grams of cholesterol and 23.22 grams of methylacetoacetate were heated at C. with water condenser for 5 hours. Then 50milliliters of methanol was added, the solution was cooled overnight at23 F., and the white solid was filtered, washed with 50 milliliters ofmethanol and dried. This product melted at 94.595.5 C. and wassubstantially pure cholesteryl acetoacetate.

EXAMPLE XL The process of Example XXXl'X was repeated at a temperatureof C. rather than 140 C. The result mg cholesterol acetate was slightlylower in purity than that obtained in Example XXXIX having a meltingpoint of 90-91 C.

EXAMPLE XLI 10 grams of crude l2-hydroxystearic acid containing 85% byweight of l2-hydroxystearic acid (the balance being largely stearicacid) and 100 milliliters of methyl acetoacetate were heated on thesteam bath for 26 hours. The unreacted methyl acetoacetate was distilledoif by heating the reaction mixture in vacuo. After distillation, thereremained 13 grams of a water white oil. Numerous crystallizations fromhexane and finally from methanol yielded silky white needles whichmelted at 31.5 to 32.5 C. This product is l2-acetoacetoxystearic acid.The corresponding esters of other hydroxy acids such as glycolic acid,lactic acid, ricinoleic acid, tartaric acid, etc. may be prepared in thesame manner. Moreover the esters of such hydroxy acids may be treated inthe same way.

The preparation of the beta-keto esters as herein described affords theopportunity of preparing a host of new compounds due to the greatreactivity of beta-keto esters. Thus beta-keto esters containing one ormore active hydrogen atoms Will in addition to the normal ester typereactions, have reactivity in the following manner:

1. Reactions involving the carbonyl group directly 2. Reactionsinvolving the enolic hydroxyl group, and

3. Reactions due to the activation of the -CH or CH2 groups between thecarbonyls.

The following are typical examples of these reactions.

1. Reactions involving the ketonic carbonyl group directly The beta-ketoesters produced according to the present invention may be reacted withhydrazines, hydroxylamines, primary and secondary amines. The followingequations illustrate the nature of reactions which occur.

These carbonyl derivatives can of course be reacted further:

NOH

H C. CHs-GCHzCOzR CHs-CH-CHzCOzR beta amino butyrate oxime crotonieester Thus the oxime of stearyl acetoacetate may be prepared by heatinga solution of 10 grams of stearyl acetoacetate and 10 grams ofhydroxylamine hydrochloride in 50 milliliters of pyridine and 60milliliters of ethanol under reflux for 3 hours. The oxime is thenprecipitated by the addition of water and recrystallized from aqueousmethanol.

Similarly the semicarbazone of cholesteryl acetoacetate may be preparedby heating a solution of 1 gram cholesteryl acetoacetate, 1 gram ofsemicarbazide hydrochlorideand 1.5 grams of anhydrous sodium acetate incc. of ethanol on the steam bath for 20 minutes, precipitating thecholesteryl acetoacetate semicarbazone by the addition of water, andcrystallizing it from a mixture of isopropyl ether and isopropanol. Thisproduct is a crystalline solid.

Moreover the other sterol acetoacetates and equivalent esters of otherbeta-keto acids herein disclosed may be reacted with semicarbazidehydrochloride in the same manner. It will also be understood thatacetoaeetates of castor oil, higher aliphatic alcohols, hydroxy acidsand their esters and hydroxy alkyd resins as well as other acetoacetatesand like keto esters produced according to this invention may be reactedwith semicarbazide hydrochloride in lieu of cholesterol acetoacetate.

Another important reaction involving the keto carbonyl group ofbeta-keto esters produced according to this invention is their reactionwith ammonia or primary or secondary amines, e. g.:

where alcohol R is the radical of the acetoacetate and R1 and R2 are theradicals of the primary or secondary amine. The following are typicalexamples of this embodiment.

EXAMPLE XLII (U) NHz CHs(CH2)aOCH2CHzOCH2CH2OC-CH= CHa EXAh/IPLE XLIIIgrams of castor oil acetoacetate was treated with ammonia in excess ofthe stoichiometric amount in a manner similar to that above described,and there was obtained a viscous, light yellow oil on evaporation of thesolvent. This material consisted largely of a triglyceride, the acidradical of which had the following structure:

EXAMPLE XLIV 60 grams of stearyl acetoacetate, 300 grams of meth anoland 50 grams of ammonium acetate were heated on a steam bath for 15minutes, and the reaction mixture was then cooled and diluted withwater. There was isolated 60 grams of a white solid which crystallizedfrom methanol in white platelets and melted at 7071 C. In absoluteethanol it showed an ultra violet light absorption maximum of log E=4.29at 274 millimicron. C, H and N analyses confirmed this structure:

EXAMPLE XLV Through a solution of 33 grams of polyethylene glycolacetoacetate (made from polyethylene glycol having a molecular weight ofabout 200) in 100 grams of methanol to which a 0.( )5 gram of ammoniumacetate had been added, ammonla gas was passed at room temperature forone hour. The reaction was somewhat exothermic. The solvent was thenstripped off under reduced pressure. There remained a light oil whichwas the beta-amino crotonate of polyethylene glycol.

The fatty acid salts of these beta-amino crotonates were found to begood emulsifiers.

It will be understood that the corresponding amino crotonate esters ofthe various other hydroxy compounds prepared according to thisinvention, including cholesterol, cortisone, stigmasterol and othersterols, glycols,

polyglycols, carbitols, hydroxyesters etc. may be prepared n the samemanner.

reacting 1053 grams of linseed oil and 2. Reactions involving the enolichydroxyl group Typical of such reactions are halogenations of betaketoesters, e. g.:

where R is the alcohol radical of the beta-keto ester.

Thus one or more active hydrogen atoms can hereplaced by halogen atoms.The following are typical examples EXAMPLE XLVI EXAMPLE XLVII An alkydresin is prepared by reacting 890 grams of refined soya oil, 220 gramsof pentaerythritol and l80 grams of glycerine with 840 grams of phthalicanhydride. All the free hydroxyl groups in this alkyd were then esterfied by heating 1000 grams of the resin with 1000 milliliters of methylacetoacetate on the steam bath for 22 hours, and removing the unreactedmethyl acetoacetate by distillation in vacuo. Solvent naphtha was thenadded to this resin to give a resin of 24% solids. Chlonne gas waspassed through the resulting solution over a per od of two hours at roomtemperature while the solut on was agitated by a stream of inert gas.After chlorination the agitation with inert gas was continued for afurther period of 6 hours to remove all HCl gas evolved. A very lightcolored resin resulted.

Acetoacetic and like esters of other alkyd resins containing freehydroxyl groups and of other higher alcohols (sterols, higher aliphaticalcohols etc.) may be treated 1n the same manner.

3. Reactions due to the activation of the CH or --CH2 groups between thecarbonyl groups The acetoacetates produced according to this inventionundergo reaction with aldehydes in an aldol type reaction:

HR'OH 1-H:O CHzCOCHCOrR CHrCOCHzCOaR CHaGOC-CO2R HR CHR' CHzCO'iIHCOaR\1 CH1 $11! CHI 4.. .0 to H-CHEF- CGHR (J H 301R C0211 1; 01B.

where R is the alcohol radical of the acetoacetate and R dical of thealdehyde. ls 'i fiu s for example, an alkyd resin was prepared by 470grams of glycerine with 893 grams of phthalic anhydride. The

resulting resin had a Gardner viscosity M at 57.6% solids in solventnaphtha, an acid value of 10.5 and a Gardner color of 9. One thousandgrams of this 57.6% solids alkyd resin was then heated on the steam bathwith 500 milliliters of methyl acetoacetate for 18 hours. All thesolvent was then removed by distillation in vacuo, and to the still hotresin 500 grams of solvent naphtha was added. The resulting resin had aGardner viscosity of U-V at 50.4% solids. Amixing of 500 grams of thisresin, 5 grams of paraformaldehyde, l milliliter of pyridine, 1 drop ofpiperidine and milliliters of solvent naphtha were then heated on thesteam bath with agitation for three hours. The reaction mixture was thenheated under vacuum until the water formed in the reaction had distilledofl azeotropically, the total distillate having a volume of 100milliliters. There remained a resin having a Gardner viscosity greaterthan Zs at 55.8% solids. Hence, by virtue of the reaction describedabove, the resin had become substantiallyfurther cross-linked, andshowed good drying properties and improved alkali resistance.

Other aldehydes, such as crotonaldehyde, acrolein, furfural,acetaldehyde and particularly those containing up to 6 carbon atoms maybe used in lieu of formaldehyde. Moreover other alkyd resins containingfree hydroxyl groups may be treated according'to this process.

Benzylic type halides and alcohols such as triphenylmethyl chloride andtriphenyl carbinol react with the beta-keto esters produced according tothis invention and new compounds are obtained according to the followingequation:

where Ar is the monovalent aryl radical.

Thus 5 grams of stearyl acetoacetate reacts with 5 grams oftriphenylmethyl chloride to give triphenylmethyl stearyl acetoacetate.

Similarly, new compounds are formed when these newly discoveredbeta-keto esters (sterol esters, alkyd esters etc.) undergo a Michaeltype reaction with alphabeta-unsaturated carbonyl compounds, e. g.:

OHs-C 0 011200 OR R'CH=CHC OR l base ont-oo-cn-ooon aqua-car on Inaddition these newly discovered beta-keto esters can react withdiazonium salts such as benzene diazonium chloride to yield compoundsakin to Hansa dyes, of interest in the synthetic dye field:

It will be understood that the above examples and discussion dealingwith the production of derivatives and compounds from beta-keto estersapply generally to the various beta-keto esters prepared according tothe process herein described. Thus any of the above mentioned sterolesters including cholesterol, stigmasterol, cortisone etc., esters ofbeta-keto acids such as acetoacetic acid, may be substituted instoichiometric amounts in lieu of the keto esters set forth in the aboveexamples for the production of the derivatives described.

While a number of the above examples are directed to the production ofacetoacetates such as sterol acetoacetates and alkyd resin acetoacetatesetc. by ester interchange reaction, it is to be understood that theseesters may be prepared by esterification by reaction of the hydroxyradical with diketene.

Although the present invention has been described with reference tocertain embodiments thereof, it is not intended that the specificdetails of such embodiments shall be regarded as limitations upon thescope of this invention except insofar as included in the accompanyingclaims.

We claim:

1. A method of forming an ester of a relatively higher alcohol and abeta-keto acid by ester interchange reaction, which comprises heating anon-catalytic mixture consisting essentially of said alcohol and anester of a lower aliphatic monohydric alcohol and said acid, at least inmolecular equivalency of said higher alcohol to effect ester interchangebetween said higher alcohol and said ester of a lower alcohol, reducingthe concentration of evolved lower alcohol sufiiciently low to maintainthe desired ester interchange, maintaining the temperature of reactionbelow the decomposition temperatures of the alcohols and the beta ketoesters, until the reaction is substantially completed and recovering theresulting ester of the higher alcohol.

2. A method of preparing an ester of a beta-keto acid and a higheralcohol which ester has a boiling point above 230 C. by esterinterchange reaction, which comprises heating a non-catalytic mixtureconsisting essentially of said higher alcohol and at least itsstoichiometric equivalent of an ester of a beta keto acid and a lowermonohydric saturated aliphatic alcohol which contains up to 4 carbonatoms and distilling oft evolved lower alcohol under conditions such asto maintain the partial pressure of the lower alcohol vapor belowatmospheric pressure during at least the final stages of the reaction.

3. A method of preparing an ester of a beta-keto acid and a higheralcohol by ester interchange reaction, which ester has a boiling pointabove 230 C., which comprises heating a non-catalytic mixture consistingessentially of said higher alcohol and at least a stoichiometricequivalent amount of an ester of a beta keto acid with a lower aliphaticsaturated monohydric alcohol containing up to 4 carbon atoms andmaintaining the temperature of the reaction mixture below about 120 C.

4. A method of preparing an ester of a beta-keto acid and a higheralcohol by ester interchange reaction which ester has a boiling pointabove 230 C., which comprises heating a non-catalytic mixture consistingessentially of said higher alcohol and at least a stoichiometricequivalent amount of an ester of a beta keto acid and a lower aliphaticsaturated monohydric alcohol containing up to 4 carbon atoms andmaintaining the temperature of the reaction mixture below about 120 C.and selectively dis tilling off evolved lower alcohol substantially asrapidly as formed.

5. The steps as defined in claim 3 in which the ester of the loweralcohol is employed in substantial molar excess with respect to thehigher alcohol.

6. The steps as defined in claim 3 in which the reaction is promoted byblowing the mixture with inert gas during the ester interchange, toremove evolved lower alcohol.

7. The steps as defined in claim 3 in which the beta keto ester of thelower alcohol is employed in a proportion of 2 to 100 moles per mole ofhigher alcohol and the excess is removed by vacuum distillation at theconclusion of the reaction.

8. The steps as defined in claim 3 in which the beta keto acid isacetoacetic acid.

9. A method of preparing an ester of a beta-keto carboxylic acid and ahigher boiling alcohol by ester interchange reaction, which comprisesforming a non-catalytic mixture consisting essentially of an ester of abeta-keto carboxylic acid of a low boiling aliphatic monohydric alcoholcontaining up to 4 carbon atoms and a higher boiling alcohol having atleast 12 carbon atoms and having no phenyl group linked to the carbinolgroup thereof, in a proportion such that at least one equivalent ofester is present per equivalent of higher boiling alcohol, heating themixture to a reaction temperature below the boiling point of the higherboiling alcohol and below the decomposition temperatures of saidalcohols and said esters and selectively removing from themixture saidlow boiling alcohol at a temperature below C. as it is evolved withoutsubstantial removal of the higher boiling alcohol until reaction iscompleted.

10. A method of preparing an ester of a beta-keto carboxylic acid and ahigher boiling alcohol by ester interchange reaction which comprisesforming a non-catalytic mixture consisting essentially of an ester of abeta-keto carboxylic acid and a low boiling aliphatic monohydric alcoholcontaining up to 4 carbon atoms and an alcohol having a boiling pointhigher than the first alcohol and having no phenyl group linked to thecarbinol group thereof, in a proportion such that at least twoequivalents of ester is present per equivalent of alcohol of higherboiling point, heating the mixture to a temperature sufficient to effectester interchange between the higher boiling alcohol and the beta ketoester of the low boiling alcohol without decomposing the esters in thesystem and without evaporating the higher boiling alcohol, and removingfrom the mixture the low boiling alcohol as it is evolved, thetemperature being maintained until the reaction is substantiallycompleted.

11. A method of preparing an ester of a beta-keto carboxylic acid and ahigher boiling aliphatic monohydric alcohol by ester interchangereaction, which comprises forming a non-catalytic mixture consistingessentially of an ester of beta-keto acid and a low boiling aliphaticmonohydric alcohol containing 1 to 4 carbon atoms and an alcohol havinga higher boiling point than the low boiling alcohol and containing atleast 6 carbon atoms and having no phenyl group linked to the carbinolgroup thereof, in a proportion such that an excess of one equivalent ofester-is present per equivalent of higher boiling alcohol, heating themixture to a temperature within a range of 80 to 120 C., selectivelyevaporating off low boiling alcohol evolved until reaction is completedand then selectively evaporating off any low boiling alcohol present andthe excess of beta keto ester of low boiling alcohol.

12. A method of forming an acetoacetic acid ester of relatively highmolecular weight by ester interchange reaction, which comprises heatinga non-catalytic mixture consisting essentially of said alcohol of highermolecular weight and an acetoacetic acid ester of an aliphatic saturatedalcohol of lower molecular Weight, the latter being in excess of molarratio with respect to said alcohol of higher molecular weight, to atemperature sumcient to distill evolved alcohol of lower molecularweight as it is formed, whereby to maintain the concentration below 5%with respect to the starting ester of alcohol of lower molecular weight,but insufficient to dehydrate the alcohol of higher molecular weight andthe acetoacetic acid esters in the system and subsequently selectivelydistilling off any residual alcohol of lower molecular weight and excessacetoacetic acid ester of said alcohol of lower molecular weight, at atemperature in the foregoing range.

13. The steps as defined in claim 12 in which the alcohol of highermolecular weight contains at least 12 carbon atoms, the alcohol of lowermolecular weight contains up to 4 carbon atoms and the temperature ofreaction is within a range of about 80 to 120 C.

14. A method of preparing an ester of a beta-keto carboxylic acid-and ahigher alcohol containing at least 12 carbon atoms in the molecule byester interchange re action, which comprises heating to a temperature of80 C. to C., a non-catalytic mixture consisting essentially' of saidalcohol and an excess of a beta-keto ester of an aliphatic monohydricalcohol containing 1 to 4 carbon atoms in the proportion of one mole ofsaid higher alcohol to an amount substantially in excess of one mole ofsaid ester to form a beta keto ester of the first mentioned alcohol byester interchange and to liberate the second mentioned alcohol.

15. A method of forming an ester of (A) a relatively higher alcoholcontaining at least 12 carbon atoms and being free of benzene groupsjoined to carbon atoms attached to a hydroxyl and (B) a beta-keto acidby ester interchange reaction, which method comprises heating anon-catalytic mixture consisting essentially of said alcohol and abeta-keto ester of a class consisting of ethyl acetoacetate and methylacetoacetate, the esters of said class being in a proportion of at leastmolar equivalency with respect to the higher alcohol, the temperaturebeing maintained below the points of decomposition of the alcohols, andthe beta-keto ester and the concentration of 21 evolved lower alcohol inthe reaction mixture being maintained sufiiciently low to attain thedesired ester interchange reaction, said conditions being maintaineduntil the reaction is substantially completed, and then recovering theresultant ester of the higher alcohol from the excess of the ester ofsaid class.

References Cited in the file of this patent UNITED STATES PATENTS 22FOREIGN PATENTS Number Country Date 592,421 Great Britain Sept. 17, 1947OTHER REFERENCES Chem. Abstracts 45 7015d 1951) (citing Carroll Proc.iilllz7gnter. Congress Pure and Applied Chem. 2, 39-48 Grog gins, UnitProcesses In Org. Synthesis, (1952) 4th Ed., pp. 616-19.

1. A METHOD OF FORMING AN ESTER OF A RELATIVELY HIGHER ALCOHOL AND ABETA-KETO ACID BY ESTER INTERCHANGE REACTION, WHICH COMPRISES HEATING ANON-CATALYTIC MIXTURE CONSISTING ESSENTIALLY OF SAID ALCOHOL AND ANESTER OF A LOWER ALIPHATIC MONOHYDRIC ALCOHOL AND SAID ACID, AT LEAST INMOLECULAR EQUIVALENCY OF SAID HIGHER ALCOHOL AND SAID ESTER INTERCHANGEBETWEEN SAID HIGHER ALCOHOL AND SAID ESTER OF A LOWER ALCOHOL, REDUCINGTHE CONCENTRATION OF EVOLVED LOWER ALCOHOL SUFFICIENTLY LOW TO MAINTAINTHE DESIRED ESTER INTERCHANGE, MAINTAINING THE TEMPERATURES OF THE OFREACTION BELOW THE DECOMPOSITION TEMPERATURES OF THE ALCOHOLS AND THEBETA KETO ESTERS, UNTIL THE REACTION IS SUBSTANTIALLY COMPLECTED ANDRECOVERING THE RESULTING ESTER OF THE HIGHER ALCOHOL.